Dostarlimab-gxly

iStock/ Afry Harvy TIGIT-targeting therapies have largely disappointed in recent months, with failed studies, terminated partnerships and shuttered businesses. Here are five biopharma players staying alive with differentiated candidates against the once promising immuno-oncology target. When GSK turned its back on development partner iTeos Therapeutics in May, a terminal countdown began for the Massachusetts-based biotech. Weeks later, time ran out and iTeos was forced to shutter operations. The biotech is only the latest casualty in a therapeutic space that is turning into a drug development wasteland. The asset that led to iTeos’ ultimate demise was belrestotug, an anti-TIGIT therapy that was being assessed for multiple solid tumors, including non-small cell lung and head and neck cancer. Though the partners did not reveal specific data, iTeos noted in May that even when used with GSK’s PD-1 blocker Jemperli, belrestotug was unable to improve progression-free survival in patients with NSCLC versus Jemperli alone. Findings in patients with head and neck cancer were likewise disappointing. Belrestotug is just one therapy in the long line of TIGIT assets that have run into insurmountable clinical roadblocks. Found in certain cells of the immune system, TIGIT —which stands for T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif domain—is a receptor with immunosuppressive effects. Under healthy circumstances, TIGIT helps regulate the release of cytokines, in turn suppressing the activity of T cells. TIGIT is overexpressed in many cancers , allowing tumor cells to inhibit the immune system’s anti-cancer response. Many biopharma players have seized on this mode of action, identifying molecules that can block TIGIT in cancers in hopes of boosting the body’s antitumor activity. But none have been successful so far, and the experience of GSK and iTeos has become the unfortunate standard. In July 2024, Roche’s tiragolumab failed to improve survival in patients with NSCLC in the closely watched SKYSCRAPER-06 trial . A few months later, another study of tiragolumab, SKYSCRAPER-01, flopped . Merck has also been stymied by TIGIT. In May 2024, the pharma scrapped a late-stage study for its anti-TIGIT antibody vibostolimab due to treatment toxicity that led to a high rate of study dropouts. Safety concerns also led to the demise of another Phase III study later that same year, this time in extensive-stage small-cell lung cancer. A key reason behind these failures, according to Padmanee Sharma, a professor in the department of Genitourinary Medical Oncology at MD Anderson Cancer Center, is that much remains unknown about how this pathway specifically works. Other proteins may also be involved in the overall TIGIT mechanism, she told BioSpace in an email, or TIGIT itself may have a role to play in other cellular functions. “TIGIT is a complex biologic target,” Sharma said. “The exact mechanism is not clear.” Still, many persist in developing a TIGIT therapy, largely because its signals of efficacy are encouraging. “Pre-clinical data indicate that TIGIT is a relevant pathway to pursue,” Sharma said, particularly for antibodies, which in lab studies have shown “anti-tumor responses.” But a more complete picture of the TIGIT pathway, including the biological pathways that regulate TIGIT, are required to set the field up for success. Here, BioSpace looks at four companies that claim differentiated approaches. Will they succeed where their peers have failed? AstraZeneca’s Sprawling Development Program for Rilvegostomig AstraZeneca’s TIGIT rilvegostomig is enrolled in an extensive late-stage development program, with 10 Phase III studies underway in NSCLC, gastric cancer, biliary tract cancer and other solid tumors, Shubh Goel, the company’s global franchise head of oncology, told BioSpace in an email. AstraZeneca is also leveraging its partnership with Daiichi Sankyo to test combinations of the TIGIT with the antibody-drug conjugate Datroway for specific subtypes of NSCLC. The goal of such a broad development push, Goel explained, is to establish rilvegostomig as a “best-in-class [immuno-oncology therapy] and the preferred IO backbone for combination therapies.” Aside from these late-stage programs, AstraZeneca is also running multiple early studies of rilvegostomig “across different tumor settings and in combination with a range of standard of care and novel agents,” Goel said. AstraZeneca’s steep investment into rilvegostomig is underpinned by what Goel called a “differentiated” mechanism of action. The molecule’s bispecific structure “optimizes dual PD1/TIGIT check point control.” Rilvegostomig first anchors itself to TIGIT before targeting PD-1, in turn “leading to enhanced immune activation and improving anti-tumor responses,” Goel explained, as compared with dosing patients with separate PD-1 and TIGIT agents. Simultaneously, rilvegostomig minimizes the unwanted depletion of effector immune cells that also express TIGIT, which results in a cleaner safety profile. Aside from a differentiated molecule, AstraZeneca is also being deliberate with its trials, focusing on patients most likely to respond to PD-1/TIGIT co-inhibition, Goel said. So far, AstraZeneca’s strategy seems to be working, at least in NSCLC. At the American Society of Clinical Oncology meeting in May, the pharma presented Phase Ib data showing that rilvegostomig plus Datroway could elicit a 57.5% confirmed overall response rate (ORR) and a 95% disease control rate as a first-line treatment for patients with advanced or metastatic NSCLC. Gilead, Arcus Forge New TIGIT Path With ‘Silent’ Killer Joining AstraZeneca in the late-stage TIGIT field are Gilead and Arcus Biosciences, which are co-developing the monoclonal antibody domvanalimab for solid tumors. Unlike rilvegostomig, domvanalimab only targets TIGIT. To address a second immune checkpoint, the partners are co-administering it with Arcus’ zimberelimab, an investigational PD-1 inhibitor, plus chemotherapy. The companies are proposing this regimen as a first-line therapy for NSCLC and upper gastrointestinal cancer—both programs are in late-stage development —and for head and neck carcinoma, currently in mid-stage studies. What sets domvanalimab apart from the rest of the TIGIT field, according to Ashish Jhingan, program strategy leader of oncology at Gilead, is its Fc-silent properties. That is, the antibody tail—the part that isn’t involved in binding to its targets—has been rendered inert. Such an approach, which goes against the current trend in the TIGIT space, minimizes the likelihood of inadvertently killing cells other than the malignant target, according to Arcus’ website . “By binding to TIGIT with Fc-silent properties, domvanalimab is believed to work by freeing up immune-activating pathways and activate immune cells to attack and kill cancer cells without depleting the peripheral regulatory T cells important in avoiding immune-related toxicity,” Jhingan told BioSpace in an email. This silent approach has so far worked well for the partners. In November 2023, they released data from the Phase II EDGE-Gastric trial, demonstrating a 59% ORR in patients after treatment with the domvanalimab-based regimen. This effect was stronger in those with high PD-L1 expression level, hitting 80% ORR. Six-month progression-free survival (PFS) at the time was 77%. Follow-up results in June 2024 showed that the domvanalimab combo could maintain its efficacy through a median of 49.4 weeks on treatment. ORR dipped only slightly to 58.5% while 12-month progression-free survival (PFS) reached 57.6% in the overall study population. Gilead and Arcus have moved domvanalimab into late-stage development. The partners are running the STAR-221 study, which will test the same regimen of domvanalimab plus zimberelimab and chemotherapy in locally advanced unresectable or metastatic HER2-negative gastric, gastroesophageal junction or esophageal adenocarcinoma. Enrollment began in June 2024 , with initial findings expected in 2026, according to Jhingan. Agenus Pushes Ahead After Losing Powerhouse Partner In May 2021, when the TIGIT space was still young, Bristol Myers Squibb sought to get ahead of its cancer competitors with a $200 million spot payment to Agenus , licensing the biotech’s anti-TIGIT therapy AGEN1777. The deal included up to $1.36 billion in development, regulatory and commercial milestone payments. But ultimately, BMS found the partnership to be more burdensome than beneficial. In August 2024, the company walked away from the pact and returned AGEN1777 to Agenus, a move that was attributed to the “broader strategic realignment of [BMS’] development pipeline,” according to an Aug. 2, 2024 SEC document from Agenus. The contract termination formally took effect on Jan. 26. According to the regulatory filing, under the partnership, Agenus and BMS were able to generate “significant safety data” in early studies, with “indications of clinical activity.” With these in hand, Agenus in August said it intends “to explore further development and/or relicensing” of AGEN1777, but has yet to provide concrete plans for the molecule. Among these development prospects is the possibility of combining the asset with Agenus’ other immuno-oncology therapies. It might take some time, however, before Agenus provides next steps for its TIGIT program, since the biotech is currently in the midst of a strategic realignment initiative aimed at lowering its cash burn to $100 million during the 2025 fiscal year. Mereo Seeks Strategic Sponsors for Etigilimab Rounding out this list is Mereo BioPharma and its troubled program etigilimab , an IgG1 monoclonal antibody designed to target TIGIT, in turn, potentially “improving the activation and effectiveness of T-cell and NK [natural killer] cell anti-tumor activity,” as per its website. Unlike Gilead and Arcus, Mereo has decided against silencing the Fc domain of etigilimab, instead deliberately giving the TIGIT therapy the added functionality of reducing regulatory T cells while also maintaining the levels of CD8-positive cytotoxic T cells. In turn, etigilimab retains the immune system’s cancer-killing action while also delivering a clean safety profile, the biotech claims . Early testing of the mechanism suggests promise in the clinic so far. Phase Ib/II data published in October 2023 demonstrated an ORR of 25% in 40 treated patients, including three who achieved a complete response and seven who saw a partial response. Eleven patients had stable disease beyond 120 days, while seven maintained clinical benefit for more than a year. Despite a promising mechanism and clinical profile, however, Mereo has struggled to rally the support it needs to take etigilimab forward. In June 2019—just months before it would be swallowed by BMS in a $74 billion acquisition—Celgene decided not to exercise an option to license etigilimab. This was despite Mereo advancing the antibody as part of a two-therapy combo with BMS’ PD-1 blocker nivolumab. Since then, and even through a mid-stage readout in 2023, the industry has continued to overlook etigilimab. In a 2024 year-end report, Mereo revealed that it has put TIGIT on the backburner . “We intend to out-license or sell etigilimab . . . to third parties for the further development, recognizing the need for greater resources to take [this asset] to market,” the company wrote.

本文梳理了近一个月（2025年4月16日～2025年5月15日）在研药物的临床试验取得不佳（研发成功率降低）进展的情况，同时，对部分药物的研究情况进行简述和分析，供研发人员参考。据统计，在检索时间范围内，共有2个药物的临床试验数据进展不佳（表1），均处于暂停阶段。适应症涉及头颈癌和非小细胞肺癌。以下对这2个药物的研究进展不佳原因进行简要介绍。表1：近一个月（2025年4月16日～2025年5月15日）临床试验数据不佳的药物Evorpacept01Evorpacept是一款SIRPα-Fc融合蛋白，旨在阻断CD47与其受体SIRPα结合，促使巨噬细胞攻击肿瘤细胞。Evorpacept也是目前少数还在开发的CD47抑制剂之一。根据ALX肿瘤公司报告的最新进展，Evorpacept与K药联用的两项Ⅱ期临床试验ASPEN-03和ASPEN-04皆未达到主要终点目标，结果显示，相比Keytruda单药，Evorpacept+Keytruda联用未能提高晚期头颈部鳞状细胞癌患者的客观缓解率（ORR）。从机制上来看，CD47是一种在正常细胞中广泛表达的膜糖蛋白，当CD47结合到巨噬细胞表面的SIRPα之后，会提供一种“别吃我”信号。当细胞表面的CD47蛋白表达水平较高时，巨噬细胞便会进行规避，从而避免对正常细胞造成“误伤”。而CD47成为肿瘤免疫治疗潜在靶标的理论基础，则在于肿瘤细胞也会通过高表达CD47来屏蔽巨噬细胞的吞噬功能。因此，只要阻断肿瘤细胞中的CD47与巨噬细胞中的SIRPα的结合作用，启动巨噬细胞对肿瘤细胞的吞噬，便可以达到抗癌的效果。基于以上机制，CD47也被称为肿瘤免疫治疗的“下一代PD-1”。在我国，宜明昂科靶向CD47的IMM01（Timdarpacept/替达派西普）是一款潜力药物，主要针对骨髓增生异常综合征（MDS）、经典霍奇金淋巴瘤（cHL）和慢性粒单核细胞白血病（CMML）3个适应症。根据2024年ASCO大会上，宜明昂科披露的MDS和cHL两个适应症数据来看，IMM01联合AZA作为一线治疗高风险MDS患者的Ⅱ期临床试验的最新结果显示，51名患者可评估疗效，完全缓解率（CR）达到33.3%，总体反应率达到64.7%；在治疗超过4个月的34名患者中，CR达到50.0%，ORR达到85.3%；而在治疗超过6个月的29名患者中，CR达到58.6%，ORR达到89.7%。此外，目前CD47靶标上，我国诸多药企在开发双抗路线，如信达的CD47/PD-L1双抗，康方的Claudin 18.2/CD47双抗，德昇济医药的HER2/CD47双抗，有望在保证安全性的同时，保持一定的肿瘤杀伤效果。Belrestotug02近日，葛兰素史克（GSK）和iTeos Therapeutics宣布，由于中期临床试验数据未能达到预期效果，双方决定终止合作开发TIGIT（T细胞免疫球蛋白和ITIM结构域）抗体Belrestotug。Belrestotug是一种针对TIGIT靶标的实验性免疫疗法，旨在通过阻断TIGIT蛋白来增强免疫系统对肿瘤的攻击能力。TIGIT是一种共抑制性受体，广泛存在于T细胞和自然杀伤细胞（NK细胞）上（图1），被认为能够抑制免疫反应，因此，成为继PD-1/L1之后的热门免疫检查点靶标。TIGIT可竞争性抑制CD226与CD155的结合，损害CD226介导的T细胞和自然杀伤（NK）细胞活化。TIGIT与其配体CD155结合会在T细胞和NK细胞中激活抑制信号。TIGIT与抗原呈递细胞（APCs）上的CD155结合会促使白细胞介素-10（IL-10）产生，减少白细胞介素-12（IL-12）生成，并间接抑制T细胞。最后，TIGIT信号传导会增强调节性T细胞（Tregs）的免疫抑制功能（图2）。图1：TIGIT、CD226、CD96和CD112R在T细胞和NK细胞中表达图2：TIGIT在免疫反应调节中的作用根据双方披露的信息，关键Ⅱ期试验结果显示，Belrestotug与抗PD-1抑制剂Jemperli联合治疗PD-L1高表达的非小细胞肺癌患者时，虽然ORR作为主要终点持续改善，但PFS（无进展生存期）未达到开发者设定的临床意义阈值。另一项针对PD-L1阳性头颈部鳞状细胞癌的Ⅱ期试验中期分析也显示，联合治疗组的疗效趋势低于预期响应率阈值，进一步加剧了研发困境。基于上述数据，GSK和iTeos决定终止所有包含belrestotug的临床试验队列，包括一项正在进行的Ⅲ期研究——该研究原计划评估Belrestotug联合Jemperli作为一线疗法在局部晚期或转移性非小细胞肺癌患者中的疗效。这一行动直接导致双方终止四年前达成的合作协议，GSK此前为此支付了6.25亿美元的预付款。TIGIT作为继PD-1/PD-L1之后的新一代免疫检查点，曾被寄予厚望。四年前GSK与iTeos达成合作时，该领域正处于热度巅峰，百时美施贵宝、吉利德、默沙东和罗氏等巨头均积极布局，试图通过阻断TIGIT-PVR信号通路扩大免疫治疗受益人群。然而，早期临床研究中观察到的疗效优势未能转化为生存获益。♡♡♡♡♡♡♡♡♡♡【参考资料】1. Informa数据库, 检索日期: 2025年5月21日.2. Insight数据库, 检索日期: 2025年5月21日.3. 药渡数据库, 检索日期：2025年5月23日.4. 药明康德、医药魔方、学术经纬、fiercebiotech、bioSeedin柏思荟、新药猎人笔记等网络公开资源.本文其它内容请见《全球药物创新快讯》2025年第4期（总第151期）。